Sexual dimorphism and the maintenance of genetic variation are two of the ubiquitous features of animal biology. Though traditional quantitative genetic analysis has provided useful insights in our understanding of these processes, a novel approach will infuse studies of these problems with renewed vigor and a fresh perspective. In this proposal, we will take advantage of a new technology, genome-wide expression profiling using cDNA microarrays, to identify genes that are responsible for intraspecific variation for sexual differentiation and dimorphism, in the fruit fly Drosophila melanogaster. We will pool the resources and diverse talents of six developmental, physiological, evolutionary, quantitative, and statistical geneticists to provide a comprehensive analysis of the sources of variance affecting transcription throughout the genome. ln the first experiment, a full diallele cross involving 10 randomly chosen, near isogenic lines, we will characterize 1) what fraction of the genome is differentially expressed between male and female adult flies; 2) what fraction is differentially expressed across genotypes, both in a sex-biased manner and across sexes; and 3) compute the variance components of these effects and the degree of additivity for the transcription of each gene. This dataset will represent the first comprehensive view of the genetic architecture of gene expression in any species. In the same lines, as well as in a set of 150 recombinant inbred lines, we will measure the phenotypes of the flies for a representative set of sexually dimorphic traits including male sex comb tooth number, abdominal pigmentation, development time, mortality, ovariole number, and susceptibility to a variety of drugs. QTL mapping experiments will be performed, and candidate genes (genes with sexually differentiated expression, which are located in the QTL) will be tested for covariation of expression of candidate genes with the relevant phenotypes. The combination of high resolution QTL mapping, quantitative expression profiling, and functional annotation will establish a powerful tool for the identification of candidate genes for each of the sexually dimorphic traits. Follow-up validation and genetic characterization of a small number of these genes will be initiated toward the end of the funding period. Throughout the proposal, we will develop novel statistical procedures that will be of utility to investigators who are trying to link expression data with quantitative susceptibility to disease in humans and vertebrate models, particularly those diseases with gender-specific susceptibility, etiology, or treatment. The genetic resources we develop will be made available to the Drosophila research community and will constitute an important resource for quantitative genetic analysis of a wide range of traits. We expect our results to have a profound impact on our understanding of the evolution of sexual dimorphism, and the role that sexual differentiation plays in the generation of phenotypic diversity.